title: New structure-activity relationships of chalcone inhibitors of breast cancer resistance protein: polyspecificity toward inhibition and critical substitutions against cytotoxicity.
abstract: Adenosine triphosphate-binding cassette subfamily G member 2 (ABCG2) plays a major role in cancer cell multidrug resistance, which contributes to low efficacy of chemotherapy. Chalcones were recently found to be potent and specific inhibitors, but unfortunately display a significant cytotoxicity. A cellular screening against ABCG2-mediated mitoxantrone efflux was performed here by flow cytometry on 54 chalcone derivatives from three different series with a wide panel of substituents. The identified leads, with submicromolar IC50 (half maximal inhibitory concentration) values, showed that the previously identified 2'-OH-4',6'-dimethoxyphenyl, as A-ring, could be efficiently replaced by a 2'-naphthyl group, or a 3',4'-methylenedioxyphenyl with lower affinity. Such a structural variability indicates 3polyspecificity of the multidrug transporter for inhibitors. At least two methoxyl groups were necessary on B-ring for optimal inhibition, but substitution at positions 3, 4, and 5 induced cytotoxicity. The presence of a large O-benzyl substituent at position 4 and a 2'-naphthyl as A-ring markedly decreased the cytotoxicity, giving a high therapeutic ratio, which constitutes a critical requirement for future in-vivo assays in animal models.
authors.affiliation: Equipe Labellisée Ligue 2013, BMSSI UMR 5086 CNRS/Université Lyon 1, Institut de Biologie et Chimie des Protéines, Lyon, France ; Department of General Microbiology, Institute of Microbiology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Luciana Pereira
authors.initials: LP
authors.lastname: Rangel
authors.forename: Evelyn
authors.initials: E
authors.lastname: Winter
authors.forename: Charlotte
authors.initials: C
authors.lastname: Gauthier
authors.forename: Raphaël
authors.initials: R
authors.lastname: Terreux
authors.forename: Louise D
authors.initials: LD
authors.lastname: Chiaradia-Delatorre
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mascarello
authors.forename: Ricardo J
authors.initials: RJ
authors.lastname: Nunes
authors.forename: Rosendo A
authors.initials: RA
authors.lastname: Yunes
authors.forename: Tania B
authors.initials: TB
authors.lastname: Creczynski-Pasa
authors.forename: Sira
authors.initials: S
authors.lastname: Macalou
authors.forename: Doriane
authors.initials: D
authors.lastname: Lorendeau
authors.forename: Hélène
authors.initials: H
authors.lastname: Baubichon-Cortay
authors.forename: Antonio
authors.initials: A
authors.lastname: Ferreira-Pereira
authors.forename: Attilio
authors.initials: A
authors.lastname: Di Pietro
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001692:Biological Transport; D047188:Chalcones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008942:Mitoxantrone / Q000493:pharmacokinetics; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D047188:Chalcones; D009363:Neoplasm Proteins; D008942:Mitoxantrone
keywords: ABC transporters; BCRP/ABCG2; cancer chemotherapy; drug transport; inhibitory chalcone derivatives; multidrug resistance transporters